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At least 1,171 records · Page 65Linked to original sources
PubMed1995

Phosphorylated neurofilament antigen redistribution in intercostal nerve subsequent to retrograde axonal transport of diphtheria toxin.

A novel enzyme-linked immunosorbent assay technique using specific monoclonal antibodies has been used to examine the proximal-distal distribution of phosphorylated neurofilament proteins (pNF) in normal feline intercostal nerve, and to compare it with that following retrograde axonal transport of the ADP-ribosylating protein diphtheria toxin (DTX) to thoracic motoneurones. The molecular target of DTX is elongation factor 2 which resides solely in the cell body. Normal intercostal nerves exhibited significantly higher amounts of the 200-kDa pNF-H, 160-kDA pNF-M, and 68-kDA pNF-L in proximal nerve than in the distal nerve. The overall content of all three triplet pNF proteins decreased 3 days after injection of DTX, but the normal proximal-distal gradient was retained. By 8 days post DTX injection, the proximal-distal gradient had reversed, with proximal nerve starved of pNF-H and pNF-M and distal nerve showing abnormally high pNF-L content. Correlative immunocytochemistry of spinal cords from normal animals verified that pNF-H and pNF-M are confined to efferent axons in the spinal grey matter, and that motoneurones are only reactive for pNF-L. At 8 days following toxin treatment, motoneurones in the ipsilateral ventral horn were strongly immunoreactive for all pNF. Contralateral motoneurones were non-reactive. Onset of abnormal perikaryal pNF immunoreactivity at 3 days precedes onset of ultrastructural cytopathology. Together these results indicate an early deficit in transference to the axon of NF proteins synthesised prior to full toxicity, probably because of a toxin-induced failure in regulation of phosphorylation-dependent NF assembly and turnover immediately prior to entry into the proximal axon. Results are discussed in relation to diphtheritic motoneuronopathy.

Animals↗
PubMed1994

Evidence that the agent of equine grass sickness may reach neurons by retrograde axonal transport.

Sera from acute and chronic cases of natural grass sickness or normal horses were injected into the parotid salivary gland of ponies. This gland receives its sympathetic innervation from the ipsilateral cranial cervical ganglion. None of the ponies showed any local or systemic signs of illness. After one week the cranial cervical ganglia, stellate and coeliaco-mesenteric ganglia were removed for histological study. Pathological changes were found only in the cranial cervical ganglion ipsilateral to a parotid salivary gland which had received an injection of grass sickness serum. Four out of five batches of test sera from cases of acute natural grass sickness were associated with chromatolytic changes in neurons; the remaining batch of serum produced no abnormalities. The most severe chromatolytic changes were induced by two samples obtained from horses whose signs of grass sickness had been present for less than 12 hours. A serum sample from a chronic case of grass sickness of three weeks duration did not produce chromatolysis but was associated with a moderately severe inflammatory infiltrate and neuronophagia in the ipsilateral cranial cervical ganglion. One batch of serum was size fractionated to separate components with molecular weights above or below 30 kDa. Only the fraction containing components above 30 kDa induced chromatolytic changes.

Acute Disease↗
PubMed2006

Axonal transport of human immunodeficiency virus type 1 envelope protein glycoprotein 120 is found in association with neuronal apoptosis.

Patients infected by human immunodeficiency virus type 1 (HIV-1) develop acquired immune deficiency syndrome-associated dementia complex (ADC), a disorder characterized by a broad spectrum of motor impairments and cognitive deficits. The number of cells in the brain that are productively infected by HIV-1 is relatively small and consists predominantly of macrophages and microglia, yet HIV-1 causes widespread neuronal loss. A better understanding of the pathogenic mechanisms mediating HIV-1 neurotoxicity is crucial for developing effective neuroprotective therapies against ADC. The HIV-1 envelope glycoprotein 120 (gp120), which is shed from the virus, is one of the agents causing neuronal cell death. However, the cellular mechanisms underlying its neurotoxic effect remain unclear. We report that gp120 injected into the rat striatum or hippocampus is sequestered by neurons and subsequently retrogradely transported to distal neurons that project to these brain areas. Cleaved caspase-3 and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling, hallmarks of apoptosis, were seen in neurons internalizing and transporting gp120. The retrograde transport of gp120 and apoptosis were mediated by the chemokine receptor CXCR4 because AMD3100, a selective CXCR4 inhibitor, blocked both events. Furthermore, colchicine or nocodazole, two inhibitors of intracellular trafficking, abolished gp120-mediated apoptosis in distal areas. These results indicate that axonal transport of gp120 might play a role in HIV-1-mediated widespread neuronal cell death.

Animals↗
PubMed1989

Early posttranslational modifications of the three neurofilament subunits in mouse retinal ganglion cells: neuronal sites and time course in relation to subunit polymerization and axonal transport.

We have characterized stages in the posttranslational processing of the three neurofilament subunits, High (NF-H), Middle (NF-M), and Low (NF-L), in retinal ganglion cells in vivo during the interval between synthesis in cell bodies within the retina and appearance of these polypeptides in axons at the level of the optic nerve (optic axons). Neurofilament proteins pulse-labeled by injecting mice intravitreally with [35S]methionine or [32P]orthophosphate, were isolated from Triton-soluble and Triton-insoluble fractions of the retina or optic axons by immunoprecipitation or immunoaffinity chromatography. Within 2 h after [35S]methionine injection, the retina contained neurofilament-immunoreactive radiolabeled proteins with apparent molecular weights of 160, 139, and 70 kDa, which co-migrated with subunits of axonal neurofilaments that were dephosphorylated in vitro with alkaline phosphatase. The two larger polypeptides were not labeled with [32P]orthophosphate, indicating that they were relatively unmodified forms of NF-H and NF-M. About 75% of the subunits were Triton-insoluble by 2 h after isotope injection, and this percentage increased to 98% by 6 h. Labeled neurofilament polypeptides appeared in optic axons as early as 2 h after injection. These subunits exhibited apparent molecular weights of 160, 139, and 70 kDa and were Triton-insoluble. The time of appearance of fully modified polypeptide forms differed for each subunit (2 h for NF-L, 6-18 h for NF-M, 18-24 h for NF-H) and was preceded by the transient appearance of intermediate forms. The modified radiolabeled subunits in optic axons 3 days after synthesis were heavily labeled with [32P]orthophosphate and exhibited the same apparent molecular weights as subunits of axonal neurofilaments (70 kDa, 145 and 140 kDa, and 195-210 kDa, respectively). Whole mounts of retina immunostained with monoclonal antibodies against NF-H in different states of phosphorylation demonstrated a transition from non-phosphorylated neurofilaments to predominantly phosphorylated ones within a region of the axon between 200 and 1000 microns downstream from the cell body. These experiments demonstrate that the addition of most phosphate groups to NF-M and NF-H takes place within a proximal region of the axon. The rapid appearance of modified forms of NF-L after synthesis may imply that processing of this subunit occurs at least partly in the cell body. The presence of a substantial pool of Triton-insoluble, unmodified subunits early after synthesis indicates that the heaviest incorporation of phosphate occurs after neurofilament proteins are polymerized.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1997

Differential display reveals transcriptional up-regulation of the motor molecules for both anterograde and retrograde axonal transport during nerve regeneration.

RNA fingerprinting using an arbitrary primed polymerase chain reaction was carried out to compare differences in expression of mRNAs between axotomized and normal hypoglossal motoneurons in the mouse. In this survey, the kinesin light chain (KLC) was identified as a nerve injury-associated molecule. This was also confirmed by in situ hybridization using hemihypoglossal nerve-transected brain sections. In order to identify the exact species of molecules belonging to the KLC family, in situ hybridization was carried out with oligonucleotide probes specific to rat KLC A, KLC B and KLC C, using the rat hypoglossal nerve injury model. In addition, expression of both ubiquitous and neuron-specific kinesin heavy chain and cytoplasmic dynein which is a retrograde motor, was also examined. Expression of all the members of the KLC (A-C) family and dynein was up-regulated during nerve regeneration, whereas the abundant expression of the neuron-specific KHC mRNA was not changed. The present results indicate that the molecules associated with both anterograde and retrograde axonal transport are up-regulated in their expression during efferent motor nerve regeneration, suggesting that the retrograde transport of growth factors and anterograde transport of vesicles, providing membrane material, could be increased during motor nerve regeneration.

Amino Acid Sequence↗
PubMed1975

Axonal transport of RNA during regeneration of the optic nerves of goldfish.

The distribution of radioactive RNA and RNA precursors in the goldfish optic tecta following intraocular injection of 3H-uridine has been studied during various stages of optic nerve regeneration. 3H-uridine was injected into the posterior chamber of the right eye 17, 30, or 60 days after both optic nerves were crushed. Five were sacrificed at time intervals ranging from 0.5 to 21 days after injection. One day prior to sacrificing, 14C-proline was also injected into the right eye as a marked of fast axonal protein transport. Seventeen to 23 days after crushing, the approximate time of nerve reconnection, the amount of radioactive RNA appearing in the left optic tectum was increased by more than ten times control values. Approximately 30 days after crushing the nerve, when the reconnected nerve is maturing, RNA values were still elevated, but significantly decreased from the earlier stage. By 60 days after crushing the optic nerve, the amounts of RNA in the left tectum was close to normal. Evidence suggesting that, at least, some of the radioactive RNA in the tectum originated from RNA transported along optic axons rather than from RNA synthesized locally in the tectum was provided by autoradiographic experiments. Autoradiograms of paraffin sections taken from the goldfish optic tecta after the intraocular injection of 3H-uridine showed a distribution of grains in a linear pattern, suggesting a distribution over the incoming fibers during the reconnection stage of regeneration. Electron microsocpic autoradiography of glutaraldehyde fixed epoxy sections confirmed that a significant number of grains (shown to be 3H-RNA) were, in fact, over regenerating optic axons. Intracranial injection of 3H-uridine, during the same stage of regeneration, on the other hand, resulted in a distribution of grains, specifically over cell perikaprya. These experiments suggest that during the reconnection phase of nerve regeneration, large amounts of RNA may be carried within regenerating optic axons as they enter the optic tectum.

Animals↗
PubMed1987

Selective axonal transport of anthracycline antibiotics.

The retrograde intraaxonal transport of several anthracycline antibiotics was assessed in the peripheral nervous system of adult mice. Despite certain chemical similarities, the intraaxonal transport of these molecules was variable and could be correlated with the structure of the aminosugar at the R-2 position. One particularly interesting compound, 4'-deoxydoxorubicin, was transported by dorsal root ganglia axons, but not by the axons of ventral horn neurons. These observations suggest that the sugar component of a molecule may be important for its intraaxonal transport in the peripheral nervous system.

Animals↗
PubMed1995

Alpha calcium/calmodulin-dependent protein kinase II immunoreactivity in corticospinal neurons: combination of axonal transport method and immunofluorescence.

A combination of either retrograde or anterograde fluorescent tracer and immunofluorescence histochemistry using the monoclonal antibody specific for the alpha isoform of calcium/calmodulin-dependent protein kinase II (CaM kinase II alpha) was employed to test whether CaM kinase II alpha is expressed in somata of corticospinal neurons and their axons over their whole course. After the injection of carbocyanine dye DiI into the hindlimb area of the primary motor cortex of the rat, corticospinal axons and their terminal arbors were anterogradely labeled: DiI-labeled corticospinal fibers proceeded caudally in the ipsilateral internal capsule, cerebral peduncle and medullary pyramid, crossed at the pyramidal decussation and descended in the ventralmost area of the contralateral dorsal funiculus of the spinal cord. These DiI-labeled corticospinal axons expressed strong CaM kinase II alpha immunoreactivity along their course. However, their terminal arbors within the gray matter of the lumbar cord were very weakly immunostained. With the injection of Fast Blue into the lumbar enlargement of the rat, somata of corticospinal neurons in layer V of the motor cortex were retrogradely labeled. The subsequent immunofluorescent histochemistry revealed that more than 80% of Fast Blue-labeled corticospinal neurons were immunostained with CaM kinase II alpha antibody. The present immunohistochemical study demonstrated that CaM kinase II alpha is strongly expressed in both somata and axons of a majority of corticospinal neurons, although we could not detect this enzyme in the corticospinal terminals in the spinal target areas.

Amidines↗
PubMed1983

Kainic acid prevents peroxidase labeling of retinal ganglion cell bodies in the rat: a possible gate in retrograde axonal transport.

Kainic acid, a neurotoxic analogue of glutamate, injected into the vitreous body of the eye, interferes with the retrograde transport of the marker enzyme horseradish peroxidase. This interference is expressed by the absence of detectable peroxidase in the cell bodies of the retinal ganglion cells and by the presence of the marker in the intraretinal portions of the optic axons. These results suggest the hypothesis of the existence of some kind of gate at the proximal portion of the axons which would control the entry of retrogradely moving material into the cell body.

Animals↗
PubMed1987

Uptake and axonal transport of horseradish peroxidase isoenzymes by different neuronal types.

The uptake and transport of basic and acidic horseradish peroxidase isoenzymes was compared in the neuromuscular, visual and olfactory systems of Xenopus larvae and postmetamorphic frogs. The concentration (w/v) of the two preparations was corrected to compensate for their difference in enzymatic activity (unit/w), which was seven-fold higher in basic horseradish peroxidase. Uptake and transport of horseradish peroxidase isoenzymes could be demonstrated with 7% basic horseradish peroxidase, but not with equal amounts of 49% acidic horseradish peroxidase in all systems investigated: retrograde transport from terminals of retinal ganglion cells, isthmotectal neurons and spinal motoneurons, as well as anterograde transganglionic transport along olfactory neurons. A very weak labelling of the same neuronal pathways by acidic horseradish peroxidase was obtained only after increasing the amount injected by approximately two-fold. Basic horseradish peroxidase isoenzymes were also preferentially taken up and transported retrogradely by broken axons of the optic nerve. When tested, similar results were obtained in both larvae and frogs suggesting that preferential uptake and transport of basic horseradish peroxidase is a general feature of all neurons and of all developmental stages. Electron microscopical analysis of the outer layers of the optic tectum revealed that, in the same experimental conditions producing no retrotrade labelling of optic axons, acidic horseradish peroxidase was rarely found to enter nerve terminals. It appears that interactions between horseradish peroxidase and neuronal membranes occur during uptake and transport and that molecular charge plays an important role, beyond non-specific fluid-phase endocytosis. We suggest that differences between horseradish peroxidase isoenzymes as neuronal tracers reflect a process of adsorptive endocytosis related to general characteristics of neuronal membranes (regardless of age) and not to specific receptor-mediated interactions characteristic of neuronal specificity.

Animals↗
PubMedDate not supplied

Neuronal uptake of iron: somatopetal axonal transport and fate of cationized and native ferritin, and iron-dextran after intramuscular injections.

Mice were injected into the muscles of the vibrissae with native ferritin (NF), cationized ferritin (CF) and iron-dextran. CF adsorbed on to the surface of the axon terminal at the neuromuscular junction, while NF did not. Both CF and NF were incorporated into vesicles and vacuoles at the synapse, but CF uptake was detected after injections at much lower concentrations than NF. In contrast to NF, CF was also found histochemically in cell bodies of facial neurones after a single i.m. injection, showing that the electrical charge of a molecule is one factor of importance for its potential to be incorporated in axons and transported somatopetally. Repeated i.m. injection of iron-dextran into suckling mice resulted in a marked iron load of Schwann cells and nerve cell bodies. This produced no signs of toxicity and the nerve fibre developed normally. Iron had disappeared from the nerve cell bodies after 25 days, while in Schwann cells it still persisted after 223 days.

Animals↗